3-benzoylphenylacetic acid and certain of its derivatives are known to possess anti-inflammatory activity. U.S. Pat. Nos. 4,254,146, 4,045,576, 4,126,635, and 4,503,073, and U.K. Patent Application Nos. 2,071,086A and 2,093,027A teach various 3-benzoylphenylacetic acids, salts and esters, and hydrates thereof, having anti-inflammatory activity. U.S. Pat. No. 4,568,695 teaches 2-amino-3-benzoylphenylethyl alcohols having anti-inflammatory activity. U.S. Pat. No. 4,313,949 teaches 2-amino-3-benzoyl-phenylacetamides having anti-inflammatory activity.
Each of the above-listed patents or patent applications, all of which are assigned in whole or in part to A. H. Robins, contains an identical disclosure regarding formulations of the 3-benzoylphenylacetic acid or acid derivative. Each of the above also contains the same disclosure regarding administration routes for the drug formulation. The only formulation examples in the A. H. Robins patents or patent applications are capsules, tablets and "injectable-2% sterile solutions," and the only administration routes mentioned are oral (as in capsules or tablets) parenteral (in the form of sterile solutions or suspensions), and, in some cases intravenous (in the form of sterile solutions). No topical or local administration is taught by any of the above-listed patents or patent applications.
Certain derivatives of 2-amino-3-benzoylbenzeneacetic acid (amfenac) and 2-amino-3-(4-chloro-benzoyl)benzeneacetic acid have also been evaluated by Walsh et al., J. Med. Chem., 33:2296-2304 (1990), in an attempt to discover nonsteroidal anti-inflammatory prodrugs with minimal or no gastrointestinal side effects upon oral administration.
In contrast, U.S. Pat. No. 4,683,242 teaches the transdermal administration of 2-amino-3-benzoylphenylacetic acids, salts, and esters, and hydrates and alcoholates thereof to control inflammation and alleviate pain.
U.S. Pat. No. 4,910,225 teaches certain benzoylphenylacetic acids for local administration to control ophthalmic, nasal or otic inflammation. Only acetic acids are disclosed in the '225 patent; no esters or amides are mentioned or taught as anti-inflammatory agents for local administration to the eyes, nose and ears.
Although benzoylphenylacetic acids are effective in suppressing ocular inflammation, their full anti-inflammatory potential has not yet been approached due to their generally slow rate of penetration through the cornea. Relatively high concentrations of these drugs are often needed to achieve corneal penetration rates sufficient to provide effective intraocular drug concentrations. Such high drug concentrations are generally not desirable as they may provoke ocular irritation and discomfort.
Additionally, the acetic acid compounds taught in the '225 patent are difficult to formulate in stable aqueous solutions. The '225 patent solves this problem by incorporating a water-soluble polymer and sulfite, and adjusting the pH to about 6.0 to 9.0, preferably about 7.5-8.5. Water soluble polymers taught by the '225 patent include polyvinyl pyrrolidone, carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, sodium salt of polyacrylic acid and so on. Polyvinyl pyrrolidone is preferred. The concentration of water soluble polymer is in the range of 0.1 to 10 w/w %. Sulfite includes sodium, potassium, magnesium, and calcium sulfite salt and so on. The concentration is in the range of about 0.1 to 1.0 w/w %.
What is needed are additional non-steroidal, topically administrable anti-inflammatory agents which are stable, non-irritating at therapeutic doses, and at least as potent as benzoylphenylacetic acids in suppressing ocular inflammation.